Modulation of the host response to influenza virus infection: The IKKe Kinase

宿主对流感病毒感染反应的调节：IKKE激酶 项目摘要 流感病毒在禽类和人类宿主中传播，每年都会导致 严重的发病率、死亡率和全球大流行的持续威胁。病毒的进化 成功在很大程度上归功于它逃避宿主豁免的能力。病毒的致病性本身被认为是 由于对感染的强大细胞反应，病毒的表达使其无效- 特定的拮抗蛋白。因此，未来抗病毒药物和疫苗设计的成功需要 彻底了解这些宿主与病原体的相互作用。最近，一种名为IKKE的IKK相关激酶被 被确认为细胞对流感病毒反应的新分子决定因素。缺乏这种激酶的小鼠 无法抑制病毒复制，因此易受感染。这些数据 提示这种激酶及其控制的细胞通路是令人兴奋的新的候选抗病毒药物 目标。这项提案侧重于三个相互关联的目标，以更好地描述IKKE和流感的作用 病毒诱导的致病性。目标1的重点是确定负责IKKE激活的激酶 在流感诱导的细胞因子信号传递之后。目的2阐明IKKE介导的功能 STAT1的磷酸化。目标3是描述IKKE水平如何调节细胞转录组 在感染流感病毒之后。因此，这一建议旨在进一步阐明细胞对 流感病毒感染，确定病毒致病性的决定因素，并发现新的成分 用于抗病毒药物和疫苗设计。

Modulation of the host response to influenza virus infection: The IKKe Kinase Project Summary Influenza viruses circulate in both avian and human hosts and account for annual outbreaks resulting in significant morbidity, mortality and the constant threat of a worldwide pandemic. The viruses' evolutionary success is largely credited to its capacity for evading host immunity. Viral pathogenicity itself is thought to result from the robust cellular response to infection that is rendered ineffective by the expression of virus- specific antagonistic proteins. Therefore, the success of future antiviral drug and vaccine design demands a thorough understanding of these host-pathogen interactions. Recently, an IKK-related kinase called IKKe was identified as a novel molecular determinant in the cellular response to influenza virus. Mice lacking this kinase were unable to inhibit virus replication and were thus rendered hypersusceptible to infection. These data suggest that this kinase, and the cellular pathway which it controls, serve as exciting new candidate antiviral targets. This proposal focuses on three interrelated aims to better characterize the role of IKKe and influenza virus-induced pathogenicity. The focus of Aim 1 is to identify the kinase responsible for IKKe activation following influenza-induced cytokine signaling. Aim 2 is to elucidate the function of IKKe-mediated phosphorylation of STAT1. Aim 3 is to characterize how the levels of IKKe modulate the cellular transcriptome following influenza virus infection. This proposal is thus designed to further elucidate the cellular response to influenza virus infection, to identify determinants of viral pathogenicity, and to discover novel components for use in antiviral drug and vaccine design.